Paradoxically enhanced endothelin-B receptor-mediated vasoconstriction in conscious old monkeys

Background-We investigated the effects of aging on the responses to endothe lin (ET) in conscious old (19.8 +/-0.6 years) and young adult (6.8 +/-0.3 y ears) monkeys and compared these results with those of other vasoconstricto rs, eg, phenylephrine (PE) and angiotensin II (Ang II). Methods and Results-The monkeys (Macaca fascicularis) were chronically inst rumented. Baseline total peripheral resistance (TPR) was not different betw een the 2 groups. As expected, TPR rose less (P <0.05) with PE (5 mug/kg) i n old monkeys (34 +/-3%) than in young monkeys (57 +/-6%): TPR also rose le ss with Ang II. Surprisingly, TPR rose more (P <0.05) with endothelin-1 (ET -1, 25 ng(.)kg(-1.)min(-1)) in old monkeys (36 +/-6%) than in young monkeys (10 +/-2%). An ET, receptor agonist, sarafotoxin (S6c, 30 ng(.)kg(-1.)min( -1)) was administered in the presence of an ET, receptor antagonist, BQ-123 (1 mg/kg). Under these conditions, TPR increased more (P <0.05) in old mon keys (59 +/- 10%) than in young monkeys (31 +/-4%). In the presence of nitr ic oxide synthase (NOS) inhibition with NW-nitro-L-arginine methyl ester (6 0 mg/kg), vasoconstriction induced by S6c no longer differed with age, beca use it was enhanced in young monkeys (P <0.05) (68'9% versus 31 +/-4%) but not in old monkeys (58 +/-6% versus 59 +/- 10%). Thus. after NOS inhibition , vasoconstrictor responses to ET were no longer enhanced in old monkeys. Conclusions-Peripheral vasoconstriction (PE and Ang II) is reduced in old m onkeys, as expected. Paradoxically, vasoconstriction induced by ET-1 was ac tually enhanced in old monkeys, which appears to be a result of impaired en dothelium-dependent vasodilation, which with ET-1 should involve the ET, re ceptor.